Dilemma in glioma

DILEMMA IN GLIOBLASTOMA
PROGRESSION
vs.
PSEUDO PROGRESSION
VS.
RADIO-NECROSIS
VS.
PSEUDO-RESPONSE
106/01/18

DR KANHU CHARAN PATRO
RADIATION ONCOLOGIST
MD, DNB[RT],FAROI[USA],MBA[HA],PDCR, CEPC
206/01/18

O
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I
VISAKHAPATNAM,1/7-MVP[AP]
306/01/18

Statistics
• Near 10 million new cases are
detected each year
• Near 20 million people living with
cancer in the world today
• Near 7 million people will die from
cancer
• Every day, around 1700 Americans
die of the disease
• 1 in 3 people will be diagnosed with
cancer in the UK and
• 1 in 4 will die from their disease
506/01/18

Lung
Breast
Colon/Rectum
Stomach
Liver
Prostate
Cervix uteri
Oesophagus
Bladder
Non-Hodgkin
Lymphoma
Leukaemia
Oral cavity
Pancreas
Kidney
Ovary
1000 800 600 400 200 0 200 400 600 800
1000
Men Women
From: D.M. Parkin The Lancet Oncology 2: 533-543 (2001)
(Thousands)
Incidence
Mortality
337
293
105
0370
241
318
446
234
165
166
471
233
133
111
76
33
121
68
113
86
47
97
101
101
34
71
192
114
810
902
558
405
255
499
398
384
204
543
279
260
227
99
93
167
144
109
81
170
116
112
57
119
5.3 million cases
3.5 million deaths
4.7 million cases
2.7 million deaths
The Global Burden of Cancer 2000
606/01/18

Radiotherapy
X ray
Surgery
PET
MRI
Chemo
? ?
706/01/18

Oncologist
Diagnosis
Treatment
Radiologist
Cytopathologist
Surgeon
HistopathologistMolecular
Pathologist
Geneticist
psychiatrist
Nursing
And
Support staff
Audit
1106/01/18

Glioblastoma (WHO grade IV)
• Previously known as glioblastoma multiforme
• Peak age of onset is 50-60yrs.
• Common in deep white matter, basal ganglia,
thalamus, rarely in cerebellum
• Grossly may appear circumscribed
• Microscopic infiltrates widely, often to other
hemisphere via corpus callosum.
• May be Multifocal
• Extracranial metastasis rare.
• Survival 1-1.5 yrs after treatment.
1206/01/18

• Central yellow or white zone of necrosis and
hemorrhage surrounded by of endothelial
hyperplasia.
• Surrounded by edematous brain (mixture of
vasogenic edema, tumour infiltrates and gliosis)
• TP53, IDH1 and IDH2 mutation less common in
primary.
• 30-40% have EFGR mutation
• MGMT mutation- favorable prognosis.
Glioblastoma (WHO grade IV)
1306/01/18

Fig 2.1B: Axial
T1 Weighted
(Wtd.) MRI
Fig 2.1A: Axial
Flair MRI
Fig 2.1C: Post-
Contrast Axial
T1 Wtd. MRI
1406/01/18

Chemo-RT schedule
• RT - Five fractions per week
• Prophylactic antiemetics
• PCP prophylaxis
• Low dose steroids with H1 blocker
• Weekly blood counts
• Give Temozolomide for a maximum of 49 days and then STOP2006/01/18

Dose modification for Concomittant
Temozolomide
2106/01/18

Methylation status as a Prognostic marker
2306/01/18

Response evaluation
• The most widely used criteria for assessing
treatment response are based on a 2D
measurement of the enhancing area on MR
imaging known as the
• Macdonald Criteria
• RANO criteria
2406/01/18

Challenges
• Recurrence/progression
• Pseudo-progression
• Radio-necrosis
• Pseudo-response
2606/01/18

MANAGEMENT DILEMMA
• CONTINUING SAME THERAPY
• 2ND
LINE THERAPY
• 2ND
SURGERY
2706/01/18

Radiation effect
• Acute
– (during radiation),
• Subacute or early-delayed
– (up to 12 weeks after radiation ends)
• Late
– (months to years post radiation)
2806/01/18

Cause-acute and sub-acute
• Both the acute and subacute types of
radiation-induced injury are thought to be
caused by vasodilation, disruption of the BBB,
and edema.
2906/01/18

Cause-Late
Blood vessel damage
ISCHEMIA
Increased capillary permeability
Fluid transudation
Brain edema
NECROSIS
3006/01/18

INCREASED ENHANCEMENT
• Increased enhancement can be induced by a
variety of non-tumoral processes, such as
treatment-related inflammation.
–Postsurgical changes,
– Ischemia,
–Subacute radiation effects,
–And radiation necrosis
Micro-ischemic lesions immediately after
surgery and radiotherapy can cause BBB
disruption
3106/01/18

TO DIFFERENTIATE
• Imaging
–MRI
–MRS
–PERFUSION
–PET-CT
–PET-MR
– DSC -dynamic susceptibility-weighted
contrast-enhanced perfusion MR imaging-rCBV
3206/01/18

MRI FINDINGS
• Edema
• New lesions
• Increased size of contrast-enhancing lesions
within the immediate vicinity of the irradiated
tumor volume.
3506/01/18

• Reduced NAA peaks
• Increased choline peak
• Increased choline/creatinine ratio
• Choline/creatinine peak>3:1 predicts high
grade tumour.
MR spectroscopy-recurrance
3606/01/18

12 MONTHS AFTER RESECTION AND RADIATION
P.C. Sundgren AJNR Am J Neuroradiol 2009;30:1469-1476
©2009 by American Society of Neuroradiology
MR spectrum shows moderately increased Cho and reduced NAA signal intensities
consistent with recurrent tumor, and
normal signal intensities of NAA, Cho, and Cr in the right hemisphere
3806/01/18

A 12 months after resection, radiation
Significantly increased Cho and almost-absent NAA signal intensities in the contrast-
enhancing areas, consistent with tumor recurrence
3906/01/18

Radio-necrosis
• Radiation necrosis typically occurs 18–24
months post-treatment and has repeatedly
been shown to be difficult to distinguish from
recurrence.
4306/01/18

18 MONTHS AFTER RESECTION AND RADIATION
Swiss cheese-like contrast enhancement surrounding the hemorrhagic lesion,
suggestive of radiation injury
4506/01/18

• An extensive metabolic peak of lipids/lactate
has been demonstrated in radiation-injured
brain tissue.
4606/01/18

OBTAINED 8 MONTHS AFTER RESECTION, RADIATION, AND CHEMOTHERAPY
MR spectroscopy spectrum shows slightly decreased
NAA and mildly increased Cho signal intensities
Bilaterally, suggestive of radiation injury.
4706/01/18

obtained 10 months after resection and radiation
Slightly increased Cho and normal NAA
and Cr signal intensities are indicative of
radiation injury,
4806/01/18

PET-CT
• FDG-PET can demonstrate differences in the analysis
of areas of radiation injury and residual/recurrent
brain tumors.
• However the reported sensitivity and specificity are
low.
• LIMITATION-The high glucose use in the brain, which
results in high background activity and by the fact
that inflammatory processes can demonstrate high
glucose metabolism on PET examinations.
4906/01/18

PSEUDO-PROGRESSION
• Essentially psPD refers to post-treatment imaging
changes in the tumor.
• Where the tumor appears larger and/or brighter
from greater contrast uptake as compared to the
pre-treatment baseline CT or MRI image.
5406/01/18

Patho-physiology
• Effective treatment can involve disruption of the
BBB, which facilitates passage of the drug and, thus,
results in an enhancement of its activity.
• This damage to the BBB can persist for several
months after treatment, showing an enhanced
lesion that appears larger than before initiation of
RT and thus simulates disease progression.
5506/01/18

Time to onset
• Pseudo-progression has been reported to
occur predominantly (in almost 60% of cases)
within the first 3 months after completing
treatment, but it may occur from the first few
weeks to 6 months after treatment
6006/01/18

O6-Methylguanine DNA MGMT Promoter
• The methylation status of the MGMT promoter has
been shown to be a potent prognostic factor in
patients with GBM.
• Methylated MGMT may be a good indicator of
therapeutic response and a better prognosis, given that
an increased overall survival has been observed in
these patients
• MGMT promoter status may predict pseudo-
progression in 90% of patients with methylated
glioblastoma.
6106/01/18

Clinical course of pseudoprogression in a 65-year-old patient with glioblastoma multiforme.
Alba A. Brandes et al. Neuro Oncol 2008;10:361-367
Copyright 2008 by the Society for Neuro-Oncology 62
Psot
sx
Post
RT
06/01/18

rCBV
• rCBV values are also useful for differentiating
treatment-related effects from viable tumor
because they can provide evidence of
neoangiogenesis in lesions.
• Recently, rCBV values have been used to
predict pseudoprogression
6506/01/18

Mangla R-Radiology 2010;256:575–84
• rCBV values in patients with GBM before and 1
month after RT+TMZ.
• In patients with pseudoprogression, There was a
41% mean decrease in rCBV,
• While cases of true tumor progression showed a
12% increase in rCBV from pretreatment to post
treatment.
– Tsien et al
• Demonstrated a reduction in rCBV in patients
with pseud-oprogression
6706/01/18

DWI -diffusion-weighted imaging
• DWI has been assessed to differentiate tumor
progression and/or residual tumor from necrosis.
• ADC values were noted to be higher in necrotic
tissue than in recurrent tumor tissue
6806/01/18

ANGIOGENESIS
• Angiogenesis is the physiological process
through which new blood vessels form
from pre-existing vessels.
• Tumors induce blood vessel growth
(angiogenesis) by secreting various growth
factors (e.g. VEGF). Growth factors such as
bFGF and VEGF can induce capillary growth
into the tumor, which some researchers
suspect supply required nutrients, allowing
for tumor expansion
7106/01/18

ANGIOGENESIS INHIBITORS
• Cediranib
• Bevacizumab
7306/01/18

MECHANISM
• The early decrease in contrast enhancement suggests a
change in vascular permeability, with a
“normalization” of the BBB, rather than a true tumor
reduction, as being the underlying cause of the
improvement.
• DRUG HOLIDAY
• Normalization of the BBB and subsequent reduction in
the vasogenic edema can result in an
• Improvement of symptoms,
– A reduction of steroid dependence, and
– An improvement of brain function and quality of life,
– Bringing clinical benefits to patients
7606/01/18

AUGUST 2015-HIGH DOSE STEROID
9006/01/18

MIBI NUCLEAR SCAN
OCTOBER 2015
9206/01/18

MIBI NUCLEAR SCAN
OCTOBER 2015
9306/01/18

MRI DIFFUSION-OCT 2015
9406/01/18

TAKE HOME MESSAGE
Progression
– New enhancing lesion
– Increase choline peak
– Decrease NAA level
– Increase perfusion
Necrosis
– Enhancing lesion
– Slight Increase choline peak
– Near normal NAA level
– Increase lipid lactate peak
– Decrease perfusion
9506/01/18

TAKE HOME MESSAGE
Pseudo-Progression
– Larger enhancing lesion
than before
– Disruption of the BBB
– Seen with in 3months
after RT
– Seen in more than 50% of
cases
– RT+TMZ>RT
– Decrease perfusion
Pseudo-Response
– Seen in treatment with VEGF
inhibitors
– Due to early normalization of
BBB/vessels
– T2 usually shows no response
9606/01/18

Dilemma in glioma

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